The overall goal of this proposal is to improve our understanding of the peripheral and central mechanisms of visceral pain processing. More specifically this project proposes to study the peripheral events that might lead to activation of visceral nociceptive afferents (both sympathetic and vagal) from the heart, lungs and esophagus using selective natural mechanical (graded pressure distention) and algesic chemical stimuli (intra-atrial, pericardial or aerosol administration to the esophagus and tracheo-bronchial tree of 5-HT, bradykinin, adenosine, histamine or PGE2). Later experiments will begin to examine the central visceral representation of these stimuli. In this application it is proposed to use a multi-disciplinary approach incorporating a variety of anatomical, pharmacological, behavioral and eletrophysiological techniques to answer four specific aims: (1) to examine and define the precise location of action of chemical and mechanical stimuli within specific organs of the thoracic viscera (i.e., heart, lungs or esophagus). (2) to characterize the adequate nociceptive stimulus, either chemical and/or mechanical, for these organs and examine potential interactions between these stimuli. (3) to define the precise afferent pathway for each of these noxious stimuli from the heart, lungs and esophagus, and examine interactions between sympathetic and vagal afferents. (4) to examine the neural substrates and the central pathways involved in mediating, or modulating, visceral pain of cardiac, respiratory or esophageal origin. This proposal represents the first systematic examination of thoracic visceral nociceptive mechanisms and will likely yield new and valuable information concerning the relative importance of chemical and mechanical activation of vagal and sympathetic afferents in mediating pain from the heart, lungs and esophagus and of the central representation and processing of noxious visceral information from the thorax.